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Mibs & Mabs
Immunotherapy to treat chronic illness
Kelly McMonigal, Pharm.D., BCPS
Pharmacy Clinical Leader
University Of Minnesota Medical Center
10/26/12
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Review general principles of biologic therapy
Review 19 individual therapies!
Discuss biologic place in therapy for
Crohn’s
 Rheumatoid Arthritis
 Psoriasis
 Macular Degeneration
 Multiple Sclerosis
 Asthma
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Positives:
•Novel MOA
•Focused target
•Potent
•Compliance help?
•Avoid absorption issues
•Few drug interactions
Negatives:
•Severe adverse effects
•IV or SQ admin
•Expensive
•Tolerance/Antibody
formation
TARGET
STRUCTURE
Anti-TNF a
Monoclonal Antibodies
Humira, Remicade, Simponi,
Cimzia, Enbrel
Anti-VEGF
Lucentis, Macugen, Avastin
Humira, Remicade, Simponi,
Cimzia, Rituxan, Soliris,
Tysabri, Xolair, Actemra,
Stelara, Ilaris, Avastin
Mab fragment
Lucentis
Miscellaneous
Rituxan, Soliris, Tysabri, Xolair,
Actemra, Stelara, Ilaris
Soluble receptor
Enbrel
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Discovered in 1975
First approved by FDA in
1980s
Use limited to acute
conditions at first
First Anti-TNFa in 1990s
rituximab
ustekinumab
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Antibody name by derivation
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O = mouse = “omab”
A = rat = “amab”
By Target:
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Tum = tumor = gemtuzumab
Vir = viral = pavilizumab
Lim = immune, daclizumab
Kin = interleuken = canakinumab
Cir = cardiovascular = abciximab
B
Y
Y
B
Y
Immortal
cell
(myeloma)
Hybridoma
Humanization
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O = mouse = omab
Xi = chimera = infliximab
ZU = humanized = certolizumab
U = human = adalimumab
Bioengineering
techniques
Purification
Amplification
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Humira®, Remicade®, Enbrel®,
Cimzia®, Simponi®
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Bind or block pro-inflammatory cytokine Tumor Necrosis
Factor (TNF)
Cause T-cell death
Inhibit T-cell activation
Suppress downstream inflammatory chemicals
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Most widely used biologics
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Used for moderate to severe disease
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Risk of infection/malignancy
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Indications – moderate to severe
Rheumatoid arthritis (RA)
 Juvenile idiopathic arthritis (JIA)
 Plaque psoriasis (P)
 Psoriatic arthritis (PA)
 Crohn’s disease (C)
 Ulcerative colitis (UC)
 Ankylosing spondylitis (AS)
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40 mg SQ every other week
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UC/C - 160 mg x 1 then 80 mg two weeks later
 Stop after 8 weeks if no remission
 May increase to 40 mg weekly if decreased response
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RA – 40 mg Qweek if no MTX
P - 80 mg x1, then 40 mg following week
1st dose by health care professional
Pen or prefilled syringe
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Indications – RA, C/UC, PA, P, AS
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Crohn’s - effective in fistulizing disease
IV infusion over 2 hours
Induction dose at 0, 2, 6 weeks
Maintenance doses Q8weeks
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RA (with MTX) – 3 mg/kg
 Increase up to 10 mg/kg or give q4 weeks if response lost
PA and AS - 5 mg/kg
 C/UC – 5 mg/kg
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 Increase to 10 mg/kg if response lost
Infusion reactions – 1-2 hours of infusion
HA, dizziness, nausea flushing, fever, chills, chest pain,
cough, cyspnea, pruritis
 Occur in ~10% of patients with stopping necessary in 2%
 Slow/stop infusion /pretreat : steroids, Tylenol and
Benadryl
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Delayed reaction at 3-14 days
similar to serum sickness : myalgias, arthralgias, fever,
rash , pruritis, HA
 may need steroid treatment
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Risk of reactions:
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Increased interval between treatments
Induction schedule 0/2/6
Maintenance immunosuppressive
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Indications – RA, PA, AS, P, JIA
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Not effective in Crohn’s treatment at same dose as used
for RA
50 mg SQ weekly
P - Twice weekly for 3 months, then weekly
 RA – 25 mg 2x/week or 50 mg SQ weekly
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Autoinjector, prefilled syringe, Multiple use vial
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Shorter t1/2 than mAbs
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Quick onset of action
Quick identification of intolerance
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C, RA
Potentially more infection risk than other TNF
agents
Induction 400 mg SQ at 0, 2, 4 weeks
Maintenance 400 mg SQ Q4weeks
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RA – can use 200 mg every other week
Prefilled syringe or single-use vial
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RA with MTX
PA, AS
not C, P
50 mg SQ Q4 weeks
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No reports of CV, MS, cytopenias, but expect similar to
other Anti-TNFa
Autoinjector or syringe
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Well tolerated
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Injection reactions with SQ
Serious adverse events (up to 6%)
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Infections, Malignancies
Neurologic reactions – Guillain-Barre, MS
New onset or worsening of CHF
Lupus-like syndrome from development of
autoantibodies – reversible
Hepatotoxicity (Remicade® warning from manufacturer )
 Monitor LFTs, Hepatitis profile
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Cytopenias
 monitor regularly
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Bacterial Sepsis, TB, Fungal, Viral, Opportunistic
Increased risk:
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Wait to start if active infections
Hep B reactivation –
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Elderly
Immunosuppressed/chronic steroids
chronic respiratory infection
Combination therapy (Humira + anakinra/abatacept)
Caution and frequent monitoring for carriers
D/C if reactivation occurs
Vaccines
No Live vaccines
Immunize adults for influenza, pneumococcal , hepatitis B, and
herpes zoster before starting.
 Children should have immunizations up-to-date before starting
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New active TB or reactivation of latent TB
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Test for latent TB before use; yearly
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Disseminated or extrapulmonary disease
Question exposure
Chest Xray
TB test (PPD or Quantiferon Gold)
Treat for latent TB prior to Anti-TNFa
Minimizes reactivation
 When LTB identified during therapy – hold TNFa*
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Remicade®/Humira® > Enbrel® for
reactivation of TB
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Invasive histoplasmosis, coccidioiodomycosis,
candidiasis, aspergillosis, blastomycosis,
pneumocystosis
Antigen and antibody testing for
histoplasmosis may be negative even with
active infection
Consider empiric antifungal therapy for severe
systemic illness
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Lymphomas
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3-fold higher rate in some studies
Aggressive disease course
Fatal cases in children treated with TNF blockers
 Most reports with adolescent males on TNF blocker for
Crohn’s
 Most had anti-TNFa + AZA or 6MP
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Non melanoma skin cancers
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Prolonged immunosuppression, PUVA therapy
Avoid anti-TNFa if recent malignancy
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Treatment options
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Potency
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5-aminosalicylates (UC, C)
Topical steroids (UC)
Antibiotics (C)
Budesonide (C)
Oral steroids (C, UC)
Immunomodulators- AZA, 6-MP, MTX (C, UC)
IV steroids (C, UC)
Anti-TNFa agents (C, UC)
CSA (UC)
Natalizumab (C)
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Goals: Treat acute disease, induce remission, and
maintain remission
Biologics for mod-severe active disease
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Biologic maintenance therapy
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Humira®, Remicade® and Cimzia® (NOT Enbrel®)
Anti-TNF therapy if no response to primary therapy steroid
refractory or bad prognosis
Improvement of active disease in 2-4 weeks with maximal at
12-16 weeks
Move to Tysabri® if anti-TNF not tolerated or non-response
Scheduled is better than episodic (avoids antibody formation)
Clinical response ~60-70%, remission 40-50%
Step Up or “top down”?
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Remicade®+AZA or Remicade® alone more effective than
AZA alone
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DMARDs + NSAID +/- Steroid = 1st line
Anti-TNFa
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Use if 1st line failure +/- MTX
Enbrel®, Remicade®, Humira® ~ equal efficacy
More effective than DMARD for joint destruction?
Work more quickly than DMARDs
If anti-TNFa failure
 Use another anti-TNFa
 Change biologic agent type (Rituxan®, Orencia®,
Actemra®)
 Kineret® (anakinra) –lower efficacy biologics
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Consider ability to do SQ injections
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Anti-CD20 molecule on B-cell surface
RA – 3rd line therapy after failure of TNF. Only
approved with MTX
1000 mg IV twice two weeks apart
Retreat q6 months
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Not recommended for use with another biologic
Lower risk of infection than some other biologics when used in
non-immunosuppressed patients
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Premedicate with steroid, Benadryl, Tylenol 30 minutes prior
Progressive Multifocal Leukoencephalopathy (PML) reported
Reactivation of Hep B
Rare anaphylactic reactions within 2 hours
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Anti- IL6
RA – 3rd line after failure of TNF agent
 Clinical improvement in as little as 2 weeks
 Used alone or in combo with DMARDs
4-8 mg/kg IV q4 weeks
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Infusion reactions, GI symptoms, hypertension,
transient neutropenia, elevated serum transaminases,
and dyslipidemia
Severe: GI perforation, serious infections,
hypersensitivity with anaphylaxis
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Costimulatory blocking fusion protein
RA – monotherapy or with DMARD
Induction 500-1000 mg IV at 0, 2, 4 weeks
Maintenance 500 -1000 mg q4 weeks OR
125 mg SQ q week
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IV and SQ apparently equivalent in efficacy
Infusion over 30 min
give 1st SQ dose starting 1 day after loading dose
some omit loading dose
Not for use with other biologics
Immediate SE – HA, HTN, dizziness, anaphylaxis (rare)
Likely increases infection risk. No association with TB
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Topical agents first line – used for minimal disease
Traditional systemic agents (MTX, CSA)
Phototherapy
Biologics
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For failure, intolerance or comorbidities with traditional systemic
agents
Choice of biologic
No clear best first choice
Response rate for cutaneous disease = Rituxan®->Humira®->
Stelara® ->Enbrel®-> Simponi®
 Often lose response over 1 year
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 add phototherapy or MTX
 Switch to another biologic
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MTX in combination? No RCT
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Anti CD2 fusion protein
Psoriasis (not PA)
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weaker efficacy than other biologics for psoriasis
15 mg IM weekly
12 week course of treatment
 Wait at least 12 weeks before additional course
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Monitoring: CD4 lymphocyte counts weekly
Hold for CD4 counts < 250 cells/L
 Discontinue if < 250 x 1 month
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Anti IL-12 and IL-23
Moderate to severe Psoriasis (not PA)
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Faster response with less frequent dosing
Induction 45mg SQ at 0, 4 weeks
Maintenance 45 mg q12 weeks
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90 mg dose if >100 kg
Injection-site reactions
Rare serious infections, malignancies and major cardiovascular events
(single report of PML)
Evaluate for TB prior
Avoid live vaccines
Angioedema and anaphylaxis – watch in patients on allergy
immunotherapy
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Mild: NSAIDs
Mod-severe: MTX or Anti-TNFa or both
MTX x 12-16 weeks, then add or switch to TNF alpha
 Combo systemic traditional agents second-line
 Enbrel®/Humira®/Remicade® -> Simponi® ->
Stelara®
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Neovascular = “wet”
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Biologic target = Vascular Endothelial Growth
Factor
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<20% of AMD, but causes 90% of severe vision loss
Prevent new blood vessel formation in subretinal
space
Biologics 1st line for neovascular AMD
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Improved visual outcomes compared to other
therapies: Verteporfin PDT, intravitreal steroids
Biologic therapies NOT for “dry”AMD
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Lucentis® (ranibizumab), Macugan® (pegaptanib)
Avastin® (bevacizumab)
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Cheaper, Off label, need consent
Intravitreal injection Q4-6 weeks
May be able to give on “as needed” schedule (CATT)
 Anesthesia and antibiotic before injection
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watch for infection prior to administration
Severe SE:
Rare endophthalmitis, retinal detachment, anaphylaxis
 Increased IOP, conjunctival hemmorrhage, eye pain,
floaters
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Anti IgE antibody
Allergic asthma, for patients
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>12 years old with moderate to severe persistent asthma
Not well controlled on an ICS
With sensitization to an airborn allergen
150-375 mcg SQ q2-4 weeks
Dose based on body weight and serum IgE levels
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Injection site pain, bruising, rare anaphylaxis
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observe for 2 hours after 1st 3 doses, then 30 min.
Pts should have EPI pen
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Anti-alpha4 integrin
Multiple Sclerosis
 Active relapsing-remitting form
 Inadequate response to other therapy
 Severe progressive form first-line
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Crohn’s
 After failure of Anti-TNFa
 D/C at 12 weeks if no response
300 mg IV q4 weeks
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1 hour infusion
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Usually causes death or neurologic disability
No treatment, prevention or cure
Highest risk patients (greatest with all 3):
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received Tysabri® for >2 years
on immunosuppressants before receiving Tysabri®
with antibodies to JC Virus
JC Virus antibody test available
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Stratify JCV Antibody ELISA test
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Administer as MONOTHERAPY
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Discontinue other immunosuppressants
 Taper steroids over 6 months
 Avoid in HIV or leukopenia
Patients must enroll in the TOUCH program
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Other SE:
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Hypersensitivity reactions
Antibody development
Hepatotoxicity
Small risk of infections
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Anti-C5 mAb
Treats Paroxysmal Nocturnal Hemoglobinuria
red cell transfusions in PNH
 Prevents anemia, fatigue, thrombosis, and
hemoglobinemia
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600 mg-1200 mg IV Q 1-4 weeks

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Infusion over 35 minutes
Meningococcal infection risk, vaccinate prior
HA (up to 50%), nausea, infusion reactions
Most expensive drug in the world!
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Anti-RANKL
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receptor activator of nuclear factor kappa-B ligand
inhibits maturation of osteoclasts
prevents bone resorption
Osteoporosis
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Males, postmenopausal females
Oncology-related
high fracture risk
60 mg subQ Q6 months
+ calcium 1000 mg/vitamin D 400 units PO daily
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Hypocalcemia - screen pre-treatment
Skin problems, infections
Jaw osteonecrosis, thigh fractures
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FDA approved
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Enbrel® ( JIA >4yo) 0.8 mg/kg weekly
Humira® (JIA >4yo)
 20 mg dose for pts 15-30 kg, 40 mg dose if > or = 30 kg
Orencia® (JIA >6yo): 10 mg/kg at weeks 0, 2, 4, then
Q4weeks
 Remicade® (C> 6 yo): 5 mg/kg IV at 0, 2, 6 weeks, then
q8 weeks
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Others used: Rituxan®, Actemra®
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Watch:
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low response to vaccines
Malignancies, esp with immunosuppression (AZA, MTX)
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mAb and fusion protein against IL-1
Indications – CAPS
Familial Cold Autoinflammatory Syndrome (FCAS)
 Muckle-Wells Syndrome (MWS)
 Neonatal-Onset Multisystem Inflammatory Disease (NOMID)
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Contraindications/SE
Dose
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Canakinumab
 2 mg/kg SQ q8weeks, may increase to 3 mg/kg
 If > 40 kg, 150 mg q8weeks
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Rilonacept 4.4 mg/kg (max 320 mg) SQ once, then
2.2 mg/kg SQ weekly
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Safety data limited
Pregnancy Class B
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Anti-TNFa
 Case reports of VACTERL
 Change therapy at conception vs use up to 30 weeks
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Pregnancy Class C
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Orencia®, Rituxan®, Actemra®
Change therapy prior to conception
Lactation:
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Safety data limited
Likely digested when taken orally by infant
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55 billion dollars in antibody sales in 2011
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#1 selling biologics were Anti-TNF Antibodies
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Antibodies in 4 of 10 top biologic sales classes
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Antibody sales > combined other biologics

insulin, erythropoetins, coagulation factors, interferons, GCSF,
enzyme replacement
“September 27, 2012 - Novartis announced today new Phase II data
showing AIN457 (secukinumab) may significantly improve
moderate-to-severe plaque psoriasis on the hands, feet and
nails...”24
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